One Magnetic Resonance Imaging (MRI) technique for quantitatively characterizing pathological changes in biological tissues is known as magnetization transfer (MT) imaging, which is based on the cross-relaxation effect. Cross-relaxation refers to the process of magnetic exchange between water and macromolecular protons, i.e., between free protons of water molecules and protons that are bound to macromolecules.
More specifically, cross-relaxation is a general magnetic relaxation mechanism, which implies the incoherent magnetization exchange between chemically nonequivalent spins due to dipolar coupling, spin diffusion, and chemical exchange. Cross-relaxation in tissues is typically described within a two-pool model, although more complicated models involve three or four exchangeable fractions. In most cases, the two-pool model provides an adequate description of experimental data and avoids excessive complexity. Within the two-pool model, cross-relaxation is a first-order equilibrium kinetic process involving the mobile water protons (free pool) and the macromolecular protons with restricted motion (bound or semisolid pool).
The protons of macromolecules are generally undetectable using MRI, because the T2 relaxation time of the protons in macromolecules is too short. However, it is possible to employ a magnetization transfer between the protons in macromolecules and the protons associated with free water molecules to detect the protons in macromolecules. The spins of macromolecules exhibit a much greater saturation in response to off-resonance radiofrequency (RF) pulses, than do the spins in free water molecules. The magnetic energy absorbed by protons in the macromolecules can be transferred to the protons in free water molecules. Since the protons in free water molecules have sufficiently long T2 relaxation times to be readily detected, this magnetization transfer process enables MRI to indirectly detect and image the macromolecules and the tissue that they comprise by attenuation of the observed signal.
A phenomenological way of characterizing the efficiency of magnetization transfer is the magnetization transfer ratio (MTR), which is calculated as a relative decrease of the signal intensity caused by off-resonance saturation. MTR is widely used in modern MRI for quantitative tissue characterization. Of the various quantitative MRI methods, MTR imaging has attracted particular attention due to its simple experimental implementation and its ability to provide global tissue characterization. However, MTR has several inherent limitations. In fact, MTR has a complex dependence on all parameters of the two-pool model, while primary factors affecting MTR can be conceptualized in terms of the approximated theory of the pulsed MT effect described in the prior art. These factors are the bound pool fraction (f) the cross-relaxation rate constant (k), and the observed longitudinal relaxation time T1. In the typical conditions of MTR imaging, MTR values are inversely proportional to a weighted sum of two factors: 1/(fT1) and 1/(kT1), and their relative weights depend on pulse sequence parameters. It is clear therefore that: (1) an expected pathological decrease of f and k can be offset by an increase of T1, which will result in a reduced sensitivity of MTR to tissue changes; (2) MTR cannot be consistently interpreted without knowledge of the pathological trends of the parameters f, k, and T1; and, (3) contributions of f, k, and T1 to MTR may vary due to instrumental factors. Another disadvantage of MTR as a biomarker is the difficulty of correcting instrumental errors. It is clear from the theoretical standpoint, and has been shown in experiments, that MTR strongly depends on B1 non-uniformities. Although attempts have been made to introduce empirical B1 correction procedures for MTR measurements, accurate correction is theoretically impossible without the knowledge of all major contributing parameters, specifically f, k, and T1.
Quantitative imaging of fundamental parameters determining the magnetization transfer effect within the two-pool model offers an attractive alternative to traditional MTR measurements, because it provides more information about pathological changes in tissues and allows more rigorous correction of experimental errors. The most comprehensive approach is based on cross-relaxation spectroscopy, or Z-spectroscopy, which employs a series of measurements with a variable offset frequency and saturation power to obtain parameters of the two-pool model (i.e., pool concentrations, exchange rate constant, and intrinsic relaxation times) from the fit of an appropriate mathematical model. The mathematical model of magnetization transfer in tissues has been refined in the prior art by implementing non-Lorentzian line shapes to describe the saturation behavior of macromolecular protons.
A traditional way of performing off-resonance saturation experiments in Z-spectroscopy involves continuous wave (CW) RF saturation, which is not applicable to human in vivo imaging due to specific absorption rate (SAR) limitations. While conventional magnetization transfer (MT) imaging rapidly evolved from CW to a less power-depositing pulsed mode, the absence of an adequate mathematical description precluded in vivo applications of a more accurate Z-spectroscopic approach in combination with the pulsed saturation regime. This problem was resolved in the prior art by incorporating pulsed off-resonance saturation into the two-pool model and by developing a mathematical formalism for data analysis. The feasibility was also demonstrated by the in vivo mapping of cross-relaxation parameters in the human brain using a pulsed MT experimental technique on clinical scanners. These measurements, however, were very time consuming, since they allowed mapping of only one or few slices with the scan time of 40-60 minutes.
An alternative group of cross-relaxation measurement methods is based on the semi-selective instantaneous excitation of either the free or bound pool using various pulse schemes, followed by the observation of bi-exponential longitudinal relaxation. A single-slice technique for mapping only one parameter (macromolecular proton fraction) with an on-resonance preparative sequence combining stimulated echo and inversion was demonstrated in vivo on the human brain. Recently, the feasibility of mapping the exchange rate and bound pool fraction based on an inversion-recovery experiment has been shown in animal imaging. Although these techniques enable single-slice scans in a reasonable time, when combined with the anatomical coverage required for clinical examinations of the whole organ (for example, the brain), their time performance becomes prohibitive for clinical use.
Practical applications of the above cross-relaxation mapping methods in clinical studies are difficult or even impossible due to a number of limitations, such as a long examination time, insufficient anatomic coverage (particularly for single-slice techniques), and a large slice thickness (typically 5-7 mm). These problems were mostly overcome by employing a newer cross-relaxation imaging method that is based on using four MT-weighted images for map reconstruction, which produces maps of key parameters of the two-pool model, specifically f and k. It is important to note that this method enables considerable improvement of parametric map quality compared to previous approaches, which resulted in maps of a generally poor quality, with a high noise level, and a lack of visualization of anatomical details. Nevertheless, further improvement in time efficiency is highly desirable, since this method, which currently provides the best time performance, requires about 25 minutes for whole-brain mapping.
A common limitation of the existing methods is the time-consuming measurements resulting from the need to use serial images to reconstruct parametric maps by applying mathematical fitting procedures. Therefore, existing methods are impractical for use in timely diagnosing patients in a clinical environment. An alternative method for direct algebraic calculation of the parametric k and f maps based upon as few as two experimental measurements would therefore clearly be desirable, since it should greatly reduce the time needed to achieve meaningful and useful information about the brain. As a next step in cross-relaxation imaging technology, the development of a simple two-point reconstruction method should greatly improve time efficiency.